960MO - Clinical outcomes and immune responses in a phase I/II study of personalized, neoantigen-directed immunotherapy in patients with advanced MSS-CRC, GEA and NSCLC

Background

Induction of a strong neoantigen-specific T-cell response may drive tumor lysis and clinical benefit in patients (pts) with poor responses to checkpoint inhibitors (CPI) alone.

Methods

Pts with advanced MSS-CRC (n=10; ≥ 2 lines of therapy), gastroesophageal adenocarcinoma (GEA; n= 10; ≥ 1 line of therapy), and NSCLC (n=2; post-CPI, ≥ 1 line of therapy) were treated with a patient-specific neoantigen-directed heterologous prime/boost vaccine leveraging 20 neoantigens selected using the EDGE^TM platform plus 30 mg SC ipilimumab and 480 mg IV nivolumab. Prime is a chimpanzee adenovirus (ChAd) and boosts are self-amplifying mRNA formulated in lipid nanoparticles and a second ChAd administration.

Results

22 pts have been treated. Treatment-related AEs and SAEs were mostly Grade 1-2 and reversible with no DLTs. All evaluated pts have a vaccine-induced, neoantigen-specific T-cell response typically evident after priming and further increased or maintained with boosts. Elicited T-cells were specific for multiple neoantigens (including epitope spreading), cytotoxic and infiltrated the tumor. The best response in 18 evaluable pts per RECIST includes 1 confirmed complete response (GEA; > 4 months [mo]), 4 stable disease (1 CRC >18 mo, 1 CRC > 9 mo, 1 CRC and 1 GEA up to 6 mo), 11 progressive disease (PD), and 2 no measurable disease. CD8⁺ T-cell responses develop over the first 1-3 mo of vaccination and 8 pts progressed within the first 9 weeks, prior to expected treatment effect. Of 9 pts treated beyond RECIST PD, 4 pts did not have confirmed PD at the next scan. In 9 pts with MSS-CRC with at least one scan, 5 were progression-free per iRECIST beyond 6 mo and 4 of the 5 showed circulating tumor DNA (ctDNA) response (decrease ≥ 50% from baseline) indicating clinical activity in MSS-CRC. Enrollment continues; data will be updated.

Conclusions

Neoantigen-directed prime/boost immunotherapy in combination with CPI is well-tolerated and generates strong and persistent T-cells to multiple neoantigens. Increases in T-cells correlate with a novel pattern of response and clinical benefit characterized by a transient spike then decline in ctDNA, tumor markers, and tumor size, notably in pts with MSS-CRC.

Clinical trial identification

NCT03639714.

Editorial acknowledgement

Legal entity responsible for the study

Gritstone bio, Inc.

Funding

Gritstone bio, Inc.

Disclosure

D.V. Catenacci: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Five Prime Therapeutics; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Personal, Advisory Board: Gritstone Oncology; Financial Interests, Personal, Advisory Board: Guardant Health; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Tempus; Financial Interests, Personal, Speaker’s Bureau: Foundation Medicine; Financial Interests, Personal, Speaker’s Bureau: Genentech; Financial Interests, Personal, Speaker’s Bureau: Guardant Health; Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Speaker’s Bureau: Merck; Financial Interests, Personal, Speaker’s Bureau: Tempus. C. Liao: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Advisory Board: Lexicon; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: QED; Financial Interests, Personal, Advisory Board: Transthera Therapeutics; Financial Interests, Personal, Advisory Board: Blueprint Medicine; Financial Interests, Personal, Advisory Board: Genentech. S. Maron: Financial Interests, Personal, Advisory Board: Basilea; Financial Interests, Personal, Advisory Board: Daiichi-Sar; Financial Interests, Personal, Advisory Board: Natera; Financial Interests, Personal, Stocks/Shares: Calithera; Non-Financial Interests, Institutional, Other: Guardant; Financial Interests, Institutional, Other: Genentech. B.J. Solomon: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Royalties: Veristrat (Biodesix); Financial Interests, Personal, Royalties: UpToDate. A. Mahipal: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: Novartis. M.L. Johnson: Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Otsuka; Financial Interests, Institutional, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: Acerta Pharma; Financial Interests, Institutional, Research Grant: Adaptimmune; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Apexigen; Financial Interests, Institutional, Research Grant: Arcus; Financial Interests, Institutional, Research Grant: Array; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Atreca; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Institutional, Research Grant: Birdie; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Checkpoint Therapeutics; Financial Interests, Institutional, Research Grant: Corvus; Financial Interests, Institutional, Research Grant: CytomX; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Dynavax; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Genocea; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Gritstone Oncology; Financial Interests, Institutional, Research Grant: Guardant; Financial Interests, Institutional, Research Grant: Hengrui; Financial Interests, Institutional, Research Grant: Immunocore; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Jounce; Financial Interests, Institutional, Research Grant: Kadmon; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Loxo; Financial Interests, Institutional, Research Grant: Lycera; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Mirati; Financial Interests, Institutional, Research Grant: Neovia; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: OncoMed; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Ribon; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Research Grant: Stem CentRx; Financial Interests, Institutional, Research Grant: Syndax; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Tarveda Therapeutics; Financial Interests, Institutional, Research Grant: TCR2 Therapeutics; Financial Interests, Institutional, Research Grant: University of Michigan; Financial Interests, Institutional, Research Grant: WindMIL. D. Carbone: Financial Interests, Institutional, Research Grant: Gritstone bio, Inc.; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Abbvie; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Biocept; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Clovis; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Foundation Medicine; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Guardant Health; Financial Interests, Personal, Advisory Board: Helsinn; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Inivata; Financial Interests, Personal, Advisory Board: Inovio; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis Oncology; Financial Interests, Personal, Advisory Board: Peregrine Pharmaceuticals; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Synta; Financial Interests, Personal, Advisory Board: Loxo; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Nexus. B. Johnson: Financial Interests, Personal, Advisory Board: Gritstone bio, Inc.; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Taiho Oncology; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Research Grant: Syntrix. S. Roychowdhury: Financial Interests, Institutional, Stocks/Shares: Johnson&Johnson; Financial Interests, Personal, Advisory Board: Abbvie; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: QED Therapeutics; Financial Interests, Personal, Research Grant: Ignyta; Financial Interests, Personal, Research Grant: Incyte; Financial Interests, Personal, Research Grant: QED Therapeutics; Financial Interests, Personal, Research Grant: Takeda. K. Mody: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Genentech/Roche; Financial Interests, Personal, Advisory Board: Merrimack; Financial Interests, Personal, Advisory Board: Vicus Therapeutics; Financial Interests, Personal, Research Grant: Agios; Financial Interests, Personal, Research Grant: Ariad; Financial Interests, Personal, Research Grant: ArQule; Financial Interests, Personal, Research Grant: FibroGen; Financial Interests, Personal, Research Grant: MedImmune; Financial Interests, Personal, Research Grant: Senhwa Biosciences; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical; Financial Interests, Personal, Research Grant: TRACON Pharma; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Gritstone Oncology; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Basilea; Financial Interests, Personal, Stocks/Shares: CytoDyn; Financial Interests, Personal, Stocks/Shares: Oncotherapeutics. E. Bournazou: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. D. Schenk: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc. S. Kounlavouth: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc. L. Kraemer: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc. G. Talbot: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc. R. Rousseau: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc.; Financial Interests, Personal, Stocks/Shares: Gritstone bio, Inc. A.R. Ferguson: Financial Interests, Personal, Full or part-time Employment: Gritstone bio, Inc.; Financial Interests, Personal, Stocks/Shares: Gritstone bio, Inc. All other authors have declared no conflicts of interest.